D₁ receptors located on striatonigral neurons and D₂ receptors located, together with A_2Areceptors, on striatopallidal neurons are known to interact functionally. Using in situ hybridization, we examined the effects of D₁ and D₂ agonists and of an A_2A antagonist on c-fos mRNA in identified striatal neurons and in globus pallidus. The full D₁agonist, SKF 82958 (1 mg/kg), induced a homogenous increase ofc-fos mRNA in the striatum. This increase occurred to a similar extent in D₁ and D₂ receptor-containing striatal neurons. Conversely, the D₂ agonist, quinelorane (2 mg/kg), decreased c-fos mRNA in these populations but increased it in globus pallidus. The adenosine A_2A receptor antagonist, SCH 58261 (5 mg/kg), also decreased c-fosmRNA in D₂ receptor-containing neurons in striatum but did not affect pallidal c-fos mRNA. Concomitant administration of either D₁ plus D₂ agonists or D₁ agonist plus A_2A antagonist caused a potentiation of c-fos mRNA in striatal neurons expressing the D₁ receptor and in globus pallidus. However, only the combination of D₁ and D₂ agonists modified the c-fos mRNA expression to a “patchy” distribution. Our data show that (1) c-fos expression can be activated through D₁ and inhibitedthrough A_2A or D₂ receptors in both striatal output pathways in normal rats, and (2) D₂ receptor stimulation as well as A_2A receptor blockade can interact with D₁ receptor activation to potentiatec-fos expression in the striatum and the globus pallidus. The data also suggest that the topological alteration ofc-fos expression after coadministration of D₁ and D₂ agonists involves D₂receptors located on interneurons or presynaptically on dopaminergic nerve terminals.